Regulation of cell migration and morphogenesis by Abl-family kinases: emerging mechanisms and physiological contexts

Abstract

The Abl-family non-receptor tyrosine kinases are essential regulators of the cytoskeleton. They transduce diverse extracellular cues into cytoskeletal rearrangements that have dramatic effects on cell motility and morphogenesis. Recent biochemical and genetic studies have revealed several mechanisms that Abl-family kinases use to mediate these effects. Abl-family kinases stimulate actin polymerization through the activation of cortactin, hematopoietic lineage cell-specific protein (HS1), WASp-and WAVE-family proteins, and Rac1. They also attenuate cell contractility by inhibiting RhoA and altering adhesion dynamics. These pathways impinge on several physiological processes, including development and maintenance of the nervous and immune systems, and epithelial morphogenesis. Elucidating how Abl-family kinases are regulated, and where and when they coordinate cytoskeletal changes, is essential for garnering a better understanding of these complex processes.

The Endocytic Fate of the Transferrin Receptor Is Regulated by c-Abl Kinase

“…First, clone 9 cells were transfected to overexpress either WT, the kinase-dead K266R/290R mutant, or the inactive 419/ 437F form (22,23) of both splice variants of c-Abl (c-Abl-1a and -1b, Fig. 2a) (24,25), and Tf internalization was allowed for 20 min before the cells were acid-stripped and further analyzed. Consistent with our findings using imatinib, expression of a FIGURE 2.…”

Parallel Genetic and Proteomic Screens Identify Msps as a CLASP–Abl Pathway Interactor in Drosophila

“…We previously showed that CLASP functions downstream of Abelson (Abl) nonreceptor tyrosine kinase (Lee et al 2004), which is a key signaling molecule that modulates the cytoskeleton downstream of numerous cell surface receptor inputs and plays essential roles in various contexts including cell motility and human disease (Van Etten 1999;Moresco and Koleske 2003;Bradley and Koleske 2009). While most cytoskeletalrelated studies of Abl have focused on its regulation of actin dynamics (Lanier and Gertler 2000;Wills et al 2002;Hernandez et al 2004;Bradley and Koleske 2009), few studies have examined its MT effectors such as CLASP and how they may be involved in the coordination of both cytoskeletal networks.…”

“…While most cytoskeletalrelated studies of Abl have focused on its regulation of actin dynamics (Lanier and Gertler 2000;Wills et al 2002;Hernandez et al 2004;Bradley and Koleske 2009), few studies have examined its MT effectors such as CLASP and how they may be involved in the coordination of both cytoskeletal networks. Additionally, we previously reported that Drosophila CLASP is necessary for accurate embryonic axon guidance at the central nervous system (CNS) midline where conserved guidance factors (Netrins and Slits) control growth cone navigation (Lee et al 2004).…”

Abl2/Abl-related Gene Stabilizes Actin Filaments, Stimulates Actin Branching by Actin-related Protein 2/3 Complex, and Promotes Actin Filament Severing by Cofilin

“…Cells use formins, Arp2/3 6 complex, and other proteins to nucleate new filaments, which grow by elongation of their barbed ends (1,2). ADF/cofilin proteins sever actin filaments, producing a new barbed end at each severing site (3).…”

“…Abl2/Arg in particular is essential for the proper formation and stability of actin-based structures, including fibroblast cell edge protrusions, cancer cell invadopodia, and dendritic spines (6 -8). In response to growth factor or adhesion receptor stimulation, Arg functions in part through phosphorylation of a number of substrates, including key cytoskeletal regulators (6). One important Arg substrate is cortactin, an actin-binding protein that stimulates the Arp2/3 complex to nucleate actin filament branches (9 -11).…”